[go: up one dir, main page]

IL174471A - Methods for synthesizing quinolinone compounds and compositions comprising such compounds - Google Patents

Methods for synthesizing quinolinone compounds and compositions comprising such compounds

Info

Publication number
IL174471A
IL174471A IL174471A IL17447106A IL174471A IL 174471 A IL174471 A IL 174471A IL 174471 A IL174471 A IL 174471A IL 17447106 A IL17447106 A IL 17447106A IL 174471 A IL174471 A IL 174471A
Authority
IL
Israel
Prior art keywords
compounds
compound
compositions
methods
synthesizing
Prior art date
Application number
IL174471A
Other languages
Hebrew (he)
Other versions
IL174471A0 (en
Original Assignee
Novartis Vaccines & Diagnostic
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Vaccines & Diagnostic filed Critical Novartis Vaccines & Diagnostic
Publication of IL174471A0 publication Critical patent/IL174471A0/en
Publication of IL174471A publication Critical patent/IL174471A/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/4709Non-condensed quinolines and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541Non-condensed thiazines containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41Preparation of salts of carboxylic acids
    • C07C51/412Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/08Lactic acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Psychiatry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Emergency Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicinal Preparation (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

A method of synthesizing a substituted or unsubstituted 4-amino-3-benzimidazolyl quinolinone compound includes reacting a first compound having the formula I with a second compound having the formula II in a suitable solvent in the presence of a sodium or potassium salt of a base. The first compound and the second compound have the following structures where the variables have the values described herein:
IL174471A 2003-11-07 2006-03-22 Methods for synthesizing quinolinone compounds and compositions comprising such compounds IL174471A (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US51791503P 2003-11-07 2003-11-07
US52642503P 2003-12-02 2003-12-02
US52642603P 2003-12-02 2003-12-02
US54601704P 2004-02-19 2004-02-19
PCT/US2004/037051 WO2005046590A2 (en) 2003-11-07 2004-11-05 Methods for synthesizing quinolinone compounds

Publications (2)

Publication Number Publication Date
IL174471A0 IL174471A0 (en) 2006-08-01
IL174471A true IL174471A (en) 2013-06-27

Family

ID=34596121

Family Applications (5)

Application Number Title Priority Date Filing Date
IL174471A IL174471A (en) 2003-11-07 2006-03-22 Methods for synthesizing quinolinone compounds and compositions comprising such compounds
IL174767A IL174767A0 (en) 2003-11-07 2006-04-04 Inhibition of fgrf3 and treatment of multiple myeloma
IL175385A IL175385A (en) 2003-11-07 2006-05-02 Lactate salt of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl] quinolin-2(1h)-one or tautomer thereof, its preparation, pharmaceutical formulation comprising the same and uses thereof
IL217114A IL217114A (en) 2003-11-07 2011-12-21 Malate or mesylate salts of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzylimidazol-2-yl] quinolin-2(1h)-one or tautomers thereof, compositions comprising the same, methods of preparation and uses thereof
IL219818A IL219818A0 (en) 2003-11-07 2012-05-16 Pharmaceutically acceptable salts of quinolinone compounds improved pharmaceutical properties

Family Applications After (4)

Application Number Title Priority Date Filing Date
IL174767A IL174767A0 (en) 2003-11-07 2006-04-04 Inhibition of fgrf3 and treatment of multiple myeloma
IL175385A IL175385A (en) 2003-11-07 2006-05-02 Lactate salt of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl] quinolin-2(1h)-one or tautomer thereof, its preparation, pharmaceutical formulation comprising the same and uses thereof
IL217114A IL217114A (en) 2003-11-07 2011-12-21 Malate or mesylate salts of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzylimidazol-2-yl] quinolin-2(1h)-one or tautomers thereof, compositions comprising the same, methods of preparation and uses thereof
IL219818A IL219818A0 (en) 2003-11-07 2012-05-16 Pharmaceutically acceptable salts of quinolinone compounds improved pharmaceutical properties

Country Status (15)

Country Link
US (7) US20050137399A1 (en)
EP (4) EP1682529A4 (en)
JP (5) JP4823914B2 (en)
KR (3) KR101167573B1 (en)
CN (1) CN102225926A (en)
AU (3) AU2004288709B2 (en)
BR (1) BRPI0416143A (en)
CA (3) CA2543820C (en)
EA (1) EA012621B1 (en)
ES (1) ES2486240T3 (en)
HK (1) HK1097444A1 (en)
IL (5) IL174471A (en)
MX (1) MXPA06004194A (en)
TW (1) TWI347940B (en)
WO (3) WO2005046590A2 (en)

Families Citing this family (94)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2334641T3 (en) 2000-09-01 2010-03-15 Novartis Vaccines And Diagnostics, Inc. AZA HETEROCICLIC DERIVATIVES AND THERAPEUTIC USE.
EA006711B1 (en) 2000-09-11 2006-02-24 Чирон Корпорейшн Quinolinone derivatives as tyrosine kinase inhibitors
US20030028018A1 (en) * 2000-09-11 2003-02-06 Chiron Coporation Quinolinone derivatives
US7825132B2 (en) * 2002-08-23 2010-11-02 Novartis Vaccines And Diagnostics, Inc. Inhibition of FGFR3 and treatment of multiple myeloma
KR20050037585A (en) 2002-08-23 2005-04-22 카이론 코포레이션 Benzimidazole quinolinones and uses thereof
NZ539425A (en) * 2002-11-13 2007-11-30 Chiron Corp Methods of treating cancer and related methods
KR101167573B1 (en) * 2003-11-07 2012-07-30 노바티스 백신즈 앤드 다이아그노스틱스 인코포레이티드 Pharmaceutically acceptable salts of quinolinone compounds having improved pharmaceutical properties
BRPI0507891A (en) * 2004-02-20 2007-07-24 Chiron Corp modulation of inflammatory and metastatic processes
US20060183750A1 (en) * 2005-01-27 2006-08-17 Chiron Corporation Treatment of metastasized tumors
US8034823B2 (en) * 2005-02-22 2011-10-11 Savvipharm Inc Method of increasing drug oral bioavailability and compositions of less toxic orotate salts
ES2732251T3 (en) * 2005-04-25 2019-11-21 Enterin Inc Crystalline Squalamine Dilactate
NZ564144A (en) 2005-05-13 2009-11-27 Novartis Ag Methods for treating drug resistant cancer
AU2012258324B2 (en) * 2005-05-17 2014-07-24 Novartis Ag Methods for synthesizing heterocyclic compounds
EP1888556B1 (en) * 2005-05-17 2011-10-26 Novartis AG Methods for synthesizing heterocyclic compounds
CN101218228A (en) * 2005-05-23 2008-07-09 诺瓦提斯公司 Crystalline and other forms of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one lactic acid salts
EP1904065A2 (en) * 2005-07-14 2008-04-02 AB Science Use of dual c-kit/fgfr3 inhibitors for treating multiple myeloma
CN101316593B (en) * 2005-11-29 2012-05-02 诺瓦提斯公司 Formulations of quinolinones
CA2627544C (en) * 2005-11-29 2015-07-07 Novartis Ag Formulations of quinolinones for the treatment of cancer
KR20080080525A (en) 2005-12-08 2008-09-04 노파르티스 아게 Effect of Inhibitors of FWFR3 on Gene Transcription
CN100488960C (en) * 2006-03-09 2009-05-20 中国药科大学 2-substituted quinolone compound and use in pharmacy
US8883790B2 (en) 2006-10-12 2014-11-11 Astex Therapeutics Limited Pharmaceutical combinations
EP2073803B1 (en) 2006-10-12 2018-09-19 Astex Therapeutics Limited Pharmaceutical combinations
KR20090119768A (en) * 2007-03-09 2009-11-19 노파르티스 아게 Melanoma Treatment
JP2010531316A (en) 2007-06-25 2010-09-24 エフ.ホフマン−ラ ロシュ アーゲー Benzimidazolamide derivatives as kinase inhibitors
GB0800855D0 (en) * 2008-01-17 2008-02-27 Syngenta Ltd Herbicidal compounds
WO2009113436A1 (en) * 2008-03-14 2009-09-17 国立大学法人千葉大学 Method for enhancing the anti-cancer activity of radioactive ray by using fgf33 gene inhibitor in combination with irradiation with the radioactive ray, and method for reducing adverse side effects of radioactive ray
PE20091628A1 (en) * 2008-03-19 2009-11-19 Novartis Ag CRYSTALLINE FORMS AND TWO SOLVATED FORMS OF LACTIC ACID SALTS OF 4-AMINO-5-FLUORO-3- [5- (4-METHYLPIPERAZIN-1-IL) -1H-BENZIMIDAZOL-2-IL] QUINOLIN-2 (1H) - ONA
EP2370417A2 (en) * 2008-11-21 2011-10-05 Millennium Pharmaceuticals, Inc. Lactate salt of 4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)quinazolin-4-yl]piperazine-1-carboxylic acid(4-isopropoxyphenyl)-amide and pharmaceutical compositions thereof for the treatment of cancer and other diseases or disorders
EP2381779A4 (en) * 2008-12-22 2012-10-24 Sanford Burnham Med Res Inst SELECTIVE ACT-INHIBITORS AND METHOD FOR THEIR USE
US8877776B2 (en) 2009-01-16 2014-11-04 Exelixis, Inc. (L)-malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
UA108618C2 (en) 2009-08-07 2015-05-25 APPLICATION OF C-MET-MODULATORS IN COMBINATION WITH THEMOSOLOMID AND / OR RADIATION THERAPY FOR CANCER TREATMENT
CA2793920A1 (en) 2010-03-26 2011-09-29 Novartis Ag Preparation of hydrated polymorphs of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactic acid salt
MX2012012058A (en) * 2010-04-16 2012-11-22 Novartis Ag Combination of organic compounds.
GB201007286D0 (en) 2010-04-30 2010-06-16 Astex Therapeutics Ltd New compounds
EA030435B1 (en) 2010-07-16 2018-08-31 Экселиксис, Инк. TABLET COMPRISING c-MET MODULATOR IN THE FORM OF CRYSTALLINE L-MALATE SALT (EMBODIMENTS), PROCESS FOR MANUFACTURING SAME AND METHOD FOR TREATING CANCER USING SAME
GB201020179D0 (en) 2010-11-29 2011-01-12 Astex Therapeutics Ltd New compounds
MX2013009116A (en) 2011-02-10 2014-01-31 Exelixis Inc Processes for preparing quinoline compounds and pharmaceutical compositions containing such compounds.
EP2524915A1 (en) * 2011-05-20 2012-11-21 Sanofi 2-Amino-3-(imidazol-2-yl)-pyridin-4-one derivatives and their use as VEGF receptor kinase inhibitors
GB201118675D0 (en) 2011-10-28 2011-12-14 Astex Therapeutics Ltd New compounds
GB201118654D0 (en) 2011-10-28 2011-12-07 Astex Therapeutics Ltd New compounds
WO2013063003A1 (en) 2011-10-28 2013-05-02 Novartis Ag Method of treating gastrointestinal stromal tumors
GB201118652D0 (en) * 2011-10-28 2011-12-07 Astex Therapeutics Ltd New compounds
GB201118656D0 (en) 2011-10-28 2011-12-07 Astex Therapeutics Ltd New compounds
WO2013088191A1 (en) 2011-12-12 2013-06-20 Institut National De La Sante Et De La Recherche Medicale (Inserm) Antagonist of the fibroblast growth factor receptor 3 (fgfr3) for use in the treatment or the prevention of skeletal disorders linked with abnormal activation of fgfr3
AU2013215251A1 (en) 2012-01-31 2014-08-14 Novartis Ag Combination of a RTK inhibitor with an anti - estrogen and use thereof for the treatment of cancer
AU2013228389A1 (en) 2012-03-08 2014-09-25 Astellas Pharma Inc. Novel FGFR3 fusion product
GB201209613D0 (en) 2012-05-30 2012-07-11 Astex Therapeutics Ltd New compounds
GB201209609D0 (en) 2012-05-30 2012-07-11 Astex Therapeutics Ltd New compounds
RU2015104537A (en) 2012-07-11 2016-08-27 Новартис Аг METHODS FOR TREATING STOMAL TUMORS OF THE GASTROINTESTINAL TRACT
CA2878987C (en) * 2012-07-17 2020-07-21 Sanofi Use of vegfr-3 inhibitors for treating hepatocellular carcinoma
EA031631B1 (en) * 2012-09-27 2019-01-31 Чугаи Сеияку Кабушики Каиша Method for treating or preventing cancer, method for selecting a patient, method for testing cancer predisposition in a subject, fusion polypeptide and uses thereof
WO2014058785A1 (en) 2012-10-10 2014-04-17 Novartis Ag Combination therapy
CN103804305A (en) * 2012-11-05 2014-05-21 韩文毅 Compound for treating eczema and application thereof
WO2014110200A1 (en) 2013-01-10 2014-07-17 Zisman Lawrence S Non-selective kinase inhibitors
DK2950649T3 (en) 2013-02-01 2020-05-04 Wellstat Therapeutics Corp AMINE COMPOUNDS WITH ANTI-INFLAMMATION, ANTI-FUNGI, ANTIPARASITY AND ANTICANCER ACTIVITY
EP2956138B1 (en) 2013-02-15 2022-06-22 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
EP3763710A1 (en) 2013-02-20 2021-01-13 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9688688B2 (en) 2013-02-20 2017-06-27 Kala Pharmaceuticals, Inc. Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
GB201307577D0 (en) 2013-04-26 2013-06-12 Astex Therapeutics Ltd New compounds
JP6483714B2 (en) 2013-10-11 2019-03-13 ローレンス エス. ジスマン, Spray-dried formulation
HUE048706T2 (en) 2013-10-14 2020-08-28 Eisai R&D Man Co Ltd Selectively substituted quinoline compounds
ES2670550T3 (en) 2013-10-14 2018-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline derivatives
CN106061261B (en) 2013-11-01 2018-04-24 卡拉制药公司 Crystal form of therapeutic compounds and application thereof
US9890173B2 (en) 2013-11-01 2018-02-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
TWI541022B (en) * 2013-12-18 2016-07-11 應克隆公司 Compounds to fibroblast growth factor receptor-3 (fgfr3) and methods of treatment
JO3512B1 (en) 2014-03-26 2020-07-05 Astex Therapeutics Ltd Quinoxaline derivatives useful as fgfr kinase modulators
PL3122358T3 (en) 2014-03-26 2021-06-14 Astex Therapeutics Ltd. Combinations of fgfr- and cmet-inhibitors for the treatment of cancer
DK3122359T3 (en) 2014-03-26 2021-03-08 Astex Therapeutics Ltd COMBINATIONS OF AN FGFR INHIBITOR AND AN IGF1R INHIBITOR
EP2977374A1 (en) * 2014-07-21 2016-01-27 Université de Strasbourg Molecules presenting dual emission properties
EP3174868B1 (en) 2014-08-01 2021-08-25 Nuevolution A/S Compounds active towards bromodomains
JOP20200201A1 (en) 2015-02-10 2017-06-16 Astex Therapeutics Ltd Pharmaceutical compositions comprising n-(3,5-dimethoxyphenyl)-n'-(1-methylethyl)-n-[3-(1-methyl-1h-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine
US20180237424A1 (en) 2015-03-03 2018-08-23 Inserm (Institut National De La Sante Et De La Recherche Medicale) Fgfr3 antagonists
US10478494B2 (en) 2015-04-03 2019-11-19 Astex Therapeutics Ltd FGFR/PD-1 combination therapy for the treatment of cancer
GB201506660D0 (en) 2015-04-20 2015-06-03 Cellcentric Ltd Pharmaceutical compounds
GB201506658D0 (en) 2015-04-20 2015-06-03 Cellcentric Ltd Pharmaceutical compounds
DK3353164T3 (en) 2015-09-23 2022-01-24 Janssen Pharmaceutica Nv BI-HETEROARYL SUBSTITUTED 1,4-BENZODIAZEPINES AND USES FOR CANCER TREATMENT
RU2747645C2 (en) 2015-09-23 2021-05-11 Янссен Фармацевтика Нв New compounds
LT3365346T (en) * 2015-10-23 2020-04-10 Esteve Pharmaceuticals, S.A. Oxa-diazaspiro compounds having activity against pain
JP6659850B2 (en) * 2015-12-31 2020-03-04 シャンハイ ファーマシューティカルズ ホールディング カンパニー,リミティド Salts of quinoline-based compounds, their crystal forms, preparation methods, compositions and uses
HRP20211801T1 (en) * 2016-01-11 2022-03-04 Merck Patent Gmbh Quinolin-2-one derivatives
TWI590475B (en) * 2016-06-17 2017-07-01 財團法人工業技術研究院 Stacked solar cell module
MX2019002629A (en) 2016-09-08 2019-10-07 Kala Pharmaceuticals Inc Crystalline forms of therapeutic compounds and uses thereof.
EP3509423A4 (en) 2016-09-08 2020-05-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
WO2018048747A1 (en) 2016-09-08 2018-03-15 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
CN107935858B (en) * 2016-10-12 2020-09-08 利尔化学股份有限公司 Preparation method of 5-fluoro-2-nitrophenol
MX2019004855A (en) 2016-10-27 2019-09-19 Pulmokine Inc Combination therapy for treating pulmonary hypertension.
JP7261752B2 (en) * 2017-06-27 2023-04-20 ヤンセン ファーマシューティカ エヌ.ベー. Novel quinolinone compound
EP3461480A1 (en) 2017-09-27 2019-04-03 Onxeo Combination of a dna damage response cell cycle checkpoint inhibitors and belinostat for treating cancer
US11384099B2 (en) 2017-11-24 2022-07-12 Janssen Pharmaceutica Nv Pyrazolopyridinone compounds
WO2019101182A1 (en) 2017-11-24 2019-05-31 Janssen Pharmaceutica Nv Pyrazolopyridinone compounds
WO2020028461A1 (en) 2018-07-31 2020-02-06 The Trustees Of Princeton University Tetrahydroquinolino derivatives for the treatment of metastatic and chemoresistant cancers
BR112021011571A2 (en) * 2018-12-26 2021-08-31 Janssen Pharmaceutica Nv THIENOPYRIDINONE COMPOUNDS
CA3213692A1 (en) 2021-04-22 2022-10-27 Mark Esposito Heterocyclic compounds and uses thereof
WO2023147513A2 (en) * 2022-01-28 2023-08-03 Washington University Compositions of autophagy modulating agents and uses thereof

Family Cites Families (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3663606A (en) * 1966-06-21 1972-05-16 Mitsui Toatsu Chemicals Organic imino-compounds
DE2363459A1 (en) 1973-12-20 1975-06-26 Basf Ag 7-Amino-quinoline cpds. - for use as optical brighteners, dyes, colour formers in copying and in printing pastes
US4287341A (en) 1979-11-01 1981-09-01 Pfizer Inc. Alkoxy-substituted-6-chloro-quinazoline-2,4-diones
US4659657A (en) * 1982-12-24 1987-04-21 Bayer Aktiengesellschaft Chromogenic and fluorogenic esters for photometric or fluorimetric determination of phosphatases or sulphatases
DE3634066A1 (en) * 1986-10-07 1988-04-21 Boehringer Mannheim Gmbh NEW 5-ALKYLBENZIMIDAZOLES, PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS
US5073492A (en) * 1987-01-09 1991-12-17 The Johns Hopkins University Synergistic composition for endothelial cell growth
JPH0699497B2 (en) 1987-04-16 1994-12-07 富士写真フイルム株式会社 Photopolymerizable composition
DE3932953A1 (en) * 1989-10-03 1991-04-11 Boehringer Mannheim Gmbh NEW 2-BICYCLO-BENZIMIDAZOLES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
US5151360A (en) * 1990-12-31 1992-09-29 Biomembrane Institute Effect of n,n,n-trimethylsphingosine on protein kinase-c activity, melanoma cell growth in vitro, metastatic potential in vivo and human platelet aggregation
GB9108547D0 (en) 1991-04-22 1991-06-05 Fujisawa Pharmaceutical Co Quinoline derivatives
US5480883A (en) * 1991-05-10 1996-01-02 Rhone-Poulenc Rorer Pharmaceuticals Inc. Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
USRE37650E1 (en) * 1991-05-10 2002-04-09 Aventis Pharmacetical Products, Inc. Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase
US5710158A (en) * 1991-05-10 1998-01-20 Rhone-Poulenc Rorer Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
US5856115A (en) * 1991-05-24 1999-01-05 Fred Hutchinson Cancer Research Center Assay for identification therapeutic agents
EP0627940B1 (en) * 1992-03-05 2003-05-07 Board of Regents, The University of Texas System Use of immunoconjugates for the diagnosis and/or therapy of vascularized tumors
JP3142378B2 (en) 1992-06-22 2001-03-07 ティーディーケイ株式会社 Organic EL device
US5330992A (en) * 1992-10-23 1994-07-19 Sterling Winthrop Inc. 1-cyclopropyl-4-pyridyl-quinolinones
US5792771A (en) * 1992-11-13 1998-08-11 Sugen, Inc. Quinazoline compounds and compositions thereof for the treatment of disease
US5763441A (en) * 1992-11-13 1998-06-09 Sugen, Inc. Compounds for the treatment of disorders related to vasculogenesis and/or angiogenesis
US5981569A (en) * 1992-11-13 1999-11-09 Yissum Research Development Company Of The Hebrew University Of Jerusalem Substituted phenylacrylonitrile compounds and compositions thereof for the treatment of disease
JPH0743896A (en) 1993-07-28 1995-02-14 Toyobo Co Ltd Photopolymerizable composition
HUT74450A (en) 1993-12-27 1996-12-30 Eisai Co Ltd Anthranilic acid derivative and pharmaceutical compns. contg. such compds.
JPH0829973A (en) 1994-07-11 1996-02-02 Toyobo Co Ltd Photopolymerized composition
JP3441246B2 (en) * 1995-06-07 2003-08-25 富士写真フイルム株式会社 Photopolymerizable composition
GB9624482D0 (en) * 1995-12-18 1997-01-15 Zeneca Phaema S A Chemical compounds
US6010711A (en) * 1996-01-26 2000-01-04 University Of Rochester Methods, articles and compositions for the pharmacologic inhibition of bone resorption with phosphodiesterase inhibitors
US6514971B1 (en) 1996-03-15 2003-02-04 Zeneca Limited Cinnoline derivatives and use as medicine
DE19610723A1 (en) 1996-03-19 1997-09-25 Bayer Ag Electroluminescent devices using glare systems
US5942385A (en) * 1996-03-21 1999-08-24 Sugen, Inc. Method for molecular diagnosis of tumor angiogenesis and metastasis
EP0934307B1 (en) * 1996-06-19 2011-04-27 Aventis Pharma Limited Substituted azabicylic compounds and their use as inhibitors of the production of tnf and cyclic amp phosphodiesterase
PL330814A1 (en) 1996-06-20 1999-06-07 Regents Board Of Compounds for and methods of delivering pharmaceutical preparations and their application
JP2001500890A (en) 1996-09-25 2001-01-23 ゼネカ リミテッド Quinoline derivatives that inhibit the action of growth factors such as VEGF
US6111110A (en) * 1996-10-30 2000-08-29 Eli Lilly And Company Synthesis of benzo[f]quinolinones
WO2001052904A2 (en) 2000-01-19 2001-07-26 Gill Parkash S Pharmaceutical compositions and methods of treatment based on vegf antisense oligonucleotides
GB9716557D0 (en) * 1997-08-06 1997-10-08 Glaxo Group Ltd Benzylidene-1,3-dihydro-indol-2-one derivatives having anti-cancer activity
DE69838172T2 (en) 1997-08-22 2008-04-10 Astrazeneca Ab OXINDOLYLCHINAZOLE DERIVATIVES AS ANGIOGENESEHEMMER
DE19756235A1 (en) * 1997-12-17 1999-07-01 Klinge Co Chem Pharm Fab New piperidinyl-substituted pyridylalkane alkene and alkane carboxylic acid amides
WO1999059636A1 (en) 1998-05-20 1999-11-25 Kyowa Hakko Kogyo Co., Ltd. Vegf activity inhibitors
US6174912B1 (en) * 1998-08-21 2001-01-16 Dupont Pharmaceuticals Company Nitrogen substituted imidazo[4,5-C]pyrazoles as corticotropin releasing hormone antagonists
DE19841985A1 (en) 1998-09-03 2000-03-09 Schering Ag New heterocyclic alkanesulfonic and alkane carboxylic acid derivatives are VEGF receptor blockers useful in treatment of e.g. psoriasis, rheumatoid arthritis, stroke, tumors and endometriosis
IL126953A0 (en) 1998-11-08 1999-09-22 Yeda Res & Dev Pharmaceutical compositions comprising porphyrins and some novel porphyrin derivatives
US20030087854A1 (en) * 2001-09-10 2003-05-08 Isis Pharmaceuticals Inc. Antisense modulation of fibroblast growth factor receptor 3 expression
EP1133474B1 (en) * 1998-12-04 2007-02-21 Bristol-Myers Squibb Company 3-substituted-4-arylquinolin-2-one derivatives as potassium channel modulators
PE20010306A1 (en) 1999-07-02 2001-03-29 Agouron Pharma INDAZOLE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM USEFUL FOR THE INHIBITION OF PROTEIN KINASE
KR100298572B1 (en) * 1999-08-19 2001-09-22 박찬구 The method for preparing 4-nitrodiphenylamine and 4-nitrosodiphenylamine from carbanilide
MXPA02003887A (en) 1999-10-19 2002-09-30 Merck & Co Inc Tyrosine kinase inhibitors.
JP2003512353A (en) * 1999-10-19 2003-04-02 メルク エンド カムパニー インコーポレーテッド Tyrosine kinase inhibitor
YU54202A (en) 2000-01-18 2006-01-16 Agouron Pharmaceuticals Inc. Indazole compounds,pharmaceutical compositions,and methods for mediating or inhibiting cell proliferation
EP1248642A4 (en) 2000-01-18 2005-05-18 Ludwig Inst Cancer Res PEPTIDOMIMETIC INHIBITOR OF VEGF AND VEGF-C AND -D
GB0001930D0 (en) 2000-01-27 2000-03-22 Novartis Ag Organic compounds
PL211834B1 (en) 2000-02-15 2012-06-29 Sugen Pyrrole substituted 2-indolinone protein kinase inhibitors
US6313138B1 (en) * 2000-02-25 2001-11-06 Merck & Co., Inc. Tyrosine kinase inhibitors
JP2003523390A (en) 2000-02-25 2003-08-05 メルク エンド カムパニー インコーポレーテッド Tyrosine kinase inhibitor
US6420382B2 (en) 2000-02-25 2002-07-16 Merck & Co., Inc. Tyrosine kinase inhibitors
PL202918B1 (en) * 2000-03-07 2009-08-31 Rush Presbyterian St Luke Compositions and methods for trapping and inactivating pathogenic microbes and spermatozoa
US6257320B1 (en) * 2000-03-28 2001-07-10 Alec Wargo Heat sink device for power semiconductors
ES2334641T3 (en) * 2000-09-01 2010-03-15 Novartis Vaccines And Diagnostics, Inc. AZA HETEROCICLIC DERIVATIVES AND THERAPEUTIC USE.
WO2002020500A2 (en) * 2000-09-01 2002-03-14 Icos Corporation Materials and methods to potentiate cancer treatment
EA006711B1 (en) * 2000-09-11 2006-02-24 Чирон Корпорейшн Quinolinone derivatives as tyrosine kinase inhibitors
US20030028018A1 (en) * 2000-09-11 2003-02-06 Chiron Coporation Quinolinone derivatives
EP1188751A1 (en) * 2000-09-13 2002-03-20 Casale Chemicals SA Process for the production of high purity melamine from urea
JP2004536113A (en) * 2001-07-03 2004-12-02 カイロン コーポレイション Indazole benzimidazole compounds as inhibitors of tyrosine kinase and serine / threonine kinase
US7495104B2 (en) * 2001-10-17 2009-02-24 Kirin Beer Kabushiki Kaisha Quinoline or quinazoline derivatives inhibiting auto-phosphorylation of fibroblast growth factor receptors
US6476068B1 (en) * 2001-12-06 2002-11-05 Pharmacia Italia, S.P.A. Platinum derivative pharmaceutical formulations
US20030159702A1 (en) * 2002-01-21 2003-08-28 Lindell Katarina E.A. Formulation and use manufacture thereof
US6822097B1 (en) * 2002-02-07 2004-11-23 Amgen, Inc. Compounds and methods of uses
US7825132B2 (en) * 2002-08-23 2010-11-02 Novartis Vaccines And Diagnostics, Inc. Inhibition of FGFR3 and treatment of multiple myeloma
US20050256157A1 (en) * 2002-08-23 2005-11-17 Chiron Corporation Combination therapy with CHK1 inhibitors
KR20050037585A (en) * 2002-08-23 2005-04-22 카이론 코포레이션 Benzimidazole quinolinones and uses thereof
EP1545529A4 (en) * 2002-09-30 2010-03-03 Bristol Myers Squibb Co Novel tyrosine kinase inhibitors
NZ539425A (en) * 2002-11-13 2007-11-30 Chiron Corp Methods of treating cancer and related methods
US6774327B1 (en) * 2003-09-24 2004-08-10 Agilent Technologies, Inc. Hermetic seals for electronic components
ATE506077T1 (en) * 2003-10-16 2011-05-15 Imclone Llc FIBROBLAST GROWTH FACTOR 1 INHIBITORS AND TREATMENT METHODS THEREOF
KR101167573B1 (en) * 2003-11-07 2012-07-30 노바티스 백신즈 앤드 다이아그노스틱스 인코포레이티드 Pharmaceutically acceptable salts of quinolinone compounds having improved pharmaceutical properties
BRPI0507891A (en) * 2004-02-20 2007-07-24 Chiron Corp modulation of inflammatory and metastatic processes
WO2006122950A1 (en) * 2005-05-18 2006-11-23 M & G Polimeri Italia S.P.A. Polyester composition

Also Published As

Publication number Publication date
EP1692085A4 (en) 2010-10-13
MXPA06004194A (en) 2006-06-28
TWI347940B (en) 2011-09-01
JP4823914B2 (en) 2011-11-24
EP1699421B1 (en) 2014-05-21
CA2544492A1 (en) 2005-05-26
IL175385A0 (en) 2008-04-13
AU2004288692A1 (en) 2005-05-26
EP1682529A4 (en) 2010-06-30
EP2762475A1 (en) 2014-08-06
CA2544492C (en) 2013-01-29
JP2007522098A (en) 2007-08-09
HK1097444A1 (en) 2007-06-29
JP2007510665A (en) 2007-04-26
IL219818A0 (en) 2012-06-28
KR101224410B1 (en) 2013-01-23
US20090181979A1 (en) 2009-07-16
IL217114A (en) 2015-04-30
JP2007510668A (en) 2007-04-26
US20140303182A1 (en) 2014-10-09
EP1682529A2 (en) 2006-07-26
EP1692085A2 (en) 2006-08-23
EA012621B1 (en) 2009-10-30
ES2486240T3 (en) 2014-08-18
IL217114A0 (en) 2012-01-31
JP2011042687A (en) 2011-03-03
KR20060111520A (en) 2006-10-27
AU2004288709A1 (en) 2005-05-26
KR20070011231A (en) 2007-01-24
AU2004288709B2 (en) 2011-01-06
WO2005046590A3 (en) 2005-10-20
JP2011162563A (en) 2011-08-25
CA2543820C (en) 2012-07-10
AU2004289672C1 (en) 2010-12-02
TW200526604A (en) 2005-08-16
US20050137399A1 (en) 2005-06-23
EP1699421A4 (en) 2010-02-17
AU2004289672B2 (en) 2010-06-24
EA200600928A1 (en) 2007-10-26
CN102225926A (en) 2011-10-26
AU2004289672A1 (en) 2005-05-26
JP4890255B2 (en) 2012-03-07
JP5214768B2 (en) 2013-06-19
BRPI0416143A (en) 2007-01-02
WO2005046589A2 (en) 2005-05-26
US20050209247A1 (en) 2005-09-22
EP1699421A2 (en) 2006-09-13
KR101167573B1 (en) 2012-07-30
CA2544186A1 (en) 2005-05-26
WO2005047244A2 (en) 2005-05-26
JP4724665B2 (en) 2011-07-13
WO2005046589A3 (en) 2007-11-22
US20130338171A1 (en) 2013-12-19
CA2543820A1 (en) 2005-05-26
IL174471A0 (en) 2006-08-01
AU2011202249B2 (en) 2013-02-21
WO2005047244A3 (en) 2006-12-21
WO2005046590A2 (en) 2005-05-26
US20130018058A1 (en) 2013-01-17
IL174767A0 (en) 2006-08-20
AU2011202249A1 (en) 2011-06-02
KR20070011241A (en) 2007-01-24
IL175385A (en) 2012-06-28
US20120277434A1 (en) 2012-11-01

Similar Documents

Publication Publication Date Title
IL174471A (en) Methods for synthesizing quinolinone compounds and compositions comprising such compounds
GB0321295D0 (en) Synthesis of protected pyrrolobenzodiazepines
WO2002020501A3 (en) Polyarylcarboxamides useful as lipid lowering agents
WO2004018451A8 (en) Pyridazinone-derivatives as pde4 inhibitors
HK1085675A1 (en) Anticancer compounds
MXPA05001354A (en) Pyrrolidinedione substituted piperidine-phthalazones as pde4 inhibitors.
GB0123589D0 (en) Organic compounds
EA200701470A1 (en) METHODS OF OBTAINING DERIVATIVES OF 4- (FENOXY-5-METHYLPYRIMIDIN-4-ILOXI) PIPERIDIN-1-CARBIC ACID AND RELATED COMPOUNDS
ZA200404752B (en) 6-aminomorphinane derivatives method for the production and use thereof
AU2251901A (en) Methods and compounds for inhibiting MRP1
SE0103710D0 (en) Compounds
MXPA04000357A (en) Amide-containing compound having improved solubility and method of improving the solubility of an amide-containing compound.
DE60330758D1 (en) CERTAIN PHARMACEUTICALLY VALUABLE SUBSTITUTED AMINO ALKYL HETEROCYCLES
EP2266971A3 (en) Hiv protease inhibiting compounds
EA199900754A1 (en) METHOD OF OBTAINING SUBSTITUTED TIAZOLIDINDION
BRPI0411664A (en) stable aqueous antiplaque oral composition
WO2003080631A8 (en) Plasma carboxypeptidase b inhibitors
TR200400293T4 (en) Synthesis of water-soluble 9-dihydro-paclitaxel derivatives of 9-dihydro-13-acetylbaccatin III.
WO2004024727A3 (en) Synthesis of indolizines
MXNL04000051A (en) Process for the production of an immunosuppressant.
TW200517394A (en) Method for stabilization of diarylvinylene compounds
DK1631533T3 (en) Hitherto unknown method for stereoselective reduction of beta-keto esters
TW200420552A (en) Dihydro-furan-2-one derivatives, their intermediates and methods of manufacture
EA200300012A1 (en) METHOD FOR PRODUCING 4-BROMANILINE DERIVATIVES
TW200510408A (en) Synthesis of indolizines

Legal Events

Date Code Title Description
FF Patent granted
KB Patent renewed
MM9K Patent not in force due to non-payment of renewal fees